FDA Grants Durvalumab Priority Review for Bladder Cancer

Durvalumab was granted a priority review to a biologics license application (BLA) by the US Food and Drug Adminsistration (FDA) for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed on standard platinum‑based chemotherapy, according to AstraZeneca, the manufacturer of the PD-L1 inhibitor.

The BLA is based on data from the phase 1/2 Study 1108, in which durvalumab induced a response rate of 46 percent in patients with PD-L1—positive advanced bladder cancer. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its final approval decision by the second quarter of 2017.

“The BLA acceptance of durvalumab in urothelial cancer is an important milestone for patients who still face considerable unmet medical need in this area. It also represents an exciting advance for our Immuno-Oncology medicines as we continue to develop chemotherapy-free treatments based on the potential clinical benefits of durvalumab, both as monotherapy and in combination,” Sean Bohen, executive vice president, Global Medicines Development, and chief medical officer at AstraZeneca, said in a statement.

Study 1108 is a dose-escalation, dose-expansion study examining durvalumab in patients with advanced solid tumors. As of the 2016 ASCO Annual Meeting, the study had recruited 1,038 patients. Durvalumab was administered at 10 mg/kg every two weeks for one year unless there was disease progression.

Tumor assessments were performed at weeks six, 12 and 16, and then every eight weeks thereafter during the treatment period. After one-year of treatment, patients entered follow-up, and those patients who progressed during follow-up were offered retreatment with durvalumab.

Safety and tolerability were the primary endpoints, with secondary endpoints including overall response rate (ORR), duration of response, progression-free survival, and overall survival. PD-L1 expression on tumor cells and tumor infiltrating immune cells was an exploratory endpoint.

As of the data cutoff of November 20, 2015, 61 patients had been enrolled in the urothelial bladder cancer cohort of the study. The first 20 patients were enrolled irrespective of PD-L1 expression. Subsequently, patients were required to have PD-L1 expression levels of at least 5 percent. Forty-patients were evaluable for response, all of whom began receiving treatment at least 12 weeks before the data cutoff.

The median age was 66 years (range, 34-81), 69 percent were male, and all patients had an ECOG performance status of 0 to 1. Sixty-two percent of patients had received one to two prior regimens for advance disease, with 31 percent having receiving three or more. Twenty-nine percent of patients had liver metastases at baseline.

The median duration of follow-up was 26 weeks (range, 3.2-59.2). The ORR among 42 evaluable patients was 31 percent (13 patients). All 13 responses were observed among the 28 PD-L1—positive patients, so the response rate in this subset was 46 percent. The disease control rate (complete response + partial response + stable disease for at least 12 weeks) was 57 percent in PD-L1–positive patients and 29 percent in PD-L1–negative patients.

Patient responses were rapid, with eight of 13 evident on the first scan. Responses were also durable, with 92.3 percent (12/13) of patients having ongoing responses at the last follow-up before the cutoff. The median duration of response was not yet reached (range, 4.1+ to 49.3+ weeks).

Treatment related all-grade adverse events (AEs) occurred in 64 percent of patients. The most common all-grade AEs, included fatigue (13 percent), diarrhea (10 percent), decreased appetite (8 percent), arthralgia (7 percent), asthenia (7 percent), nausea (7 percent) and pyrexia (7 percent).

Grade 3 AEs included acute kidney injury (2 percent), infusion-related reaction (2 percent) and tumor flare (2 percent), with only acute kidney injury resulting in treatment discontinuation. There were no grade 4 or 5 treatment-related AEs.

In February 2016, the FDA granted a breakthrough therapy designation to durvalumab as a treatment for patients with PD-L1—positive inoperable or metastatic urothelial bladder cancer following progression on prior treatment with a platinum-based regimen.

Durvalumab is also being evaluated as a single agent and in combination with tremelimumab in the phase 3 DANUBE trial in the frontline setting for patients with metastatic urothelial carcinoma, regardless of their eligibility for cisplatin-based chemotherapy.

More than 30 other ongoing trials are evaluating various combinations of durvalumab with other immunotherapies and targeted agents.